Coatings for the controllable release of antimicrobial metal ions

ABSTRACT

Antimicrobial metal ion coatings. In particular, described herein are coatings including an anodic metal (e.g., silver and/or zinc and/or copper) that is co-deposited with a cathodic metal (e.g., palladium, platinum, gold, molybdenum, titanium, iridium, osmium, niobium or rhenium) on a substrate so that the anodic metal is galvanically released as antimicrobial ions when the apparatus is exposed to a bodily fluid. The anodic metal may be at least about 25 percent by volume of the coating, resulting in a network of anodic metal with less than 20% of the anodic metal in the coating fully encapsulated by cathodic metal.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent claims priority as a continuation-in-part to U.S. patentapplication Ser. No. 14/569,545, filed on Dec. 12, 2014 and titled“BIOABSORBABLE SUBSTRATES AND SYSTEMS THAT CONTROLLABLY RELEASEANTIMICROBIAL METAL IONS,” which is a continuation of U.S. patentapplication Ser. No. 14/302,352, filed on Jun. 11, 2014 and titled“BIOABSORBABLE SUBSTRATES AND SYSTEMS THAT CONTROLLABLY RELEASEANTIMICROBIAL METAL IONS,” now U.S. Pat. No. 8,927,004. This patentapplication also claims priority to U.S. Provisional Patent ApplicationNo. 62/059,714, filed on Oct. 3, 2014 and titled “COATINGS FOR THECONTROLLABLE RELEASE OF ANTIMICROBIAL METAL IONS.” Each of these patentsand patent application is herein incorporated by reference in itsentirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Described herein are substrates having antimicrobial metal ion coatings.In particular, described herein are substrates that are coated with ananodic metal (e.g., silver and/or zinc and/or copper) that isco-deposited with a cathodic metal (e.g., palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium or rhenium) on thesubstrate to form a continuous path of interconnected veins of anodicmetal within the matrix of cathodic metal or a continuous path ofinterconnected veins of cathodic metal within the matrix of anodicmetal, wherein the continuous path extends from an outer surface of thecoating to the substrate. Thus, the antimicrobial anodic metal (e.g.,silver, zinc, copper) may be galvanically released as antimicrobial ionswhen the coated substrates is contacted by a conductive fluidenvironment, including when inserted into a subject's body.

BACKGROUND

Antimicrobial or antibiotic agents are widely used to treat as well asto prevent infection. In particular, silver is known to be antimicrobialand has been used (primarily as a coating) in various medical deviceswith limited success. Both active (e.g., by application of electricalcurrent) and passive (e.g., galvanic) release of silver ions have beenproposed for use in the treatment and prevention of infection. However,the use of silver-releasing implants have been limited because of thedifficulty in controlling and distributing the release of silver ions aswell as the difficulty in maintaining a therapeutically relevantconcentration of silver ions in an appropriate body region. Zinc sharesmany of the same antimicrobial properties of silver, but has been lesscommonly used, and thus even less is known about how to control theamount and distribution of the release of silver ions to treat and/orprevent infection.

It would be highly beneficial to use an antimicrobial agent such assilver and/or zinc as part of an implant, including a bioabsorbableimplant, in part because the risk of acquiring infections frombioabsorbable materials in medical devices is very high. Many medicalapplications exist for bioabsorbable materials including: wound closure(e.g., sutures, staples, adhesives), tissue repair (e.g., meshes, suchas for hernia repair), prosthetic devices (e.g., internal bone fixationdevices, etc.), tissue engineering (e.g., engineered blood vessels,skin, bone, cartilage, liver, etc.) and controlled drug delivery systems(such as microcapsules and ion-exchange resins). The use ofbioabsorbable materials in medical applications such as these may reducetissue or cellular irritation and the induction of an inflammatoryresponse.

Bioabsorbable materials for medical applications are well known. Forexample, synthetic bioabsorbable polymers may includepolyesters/polylactones such as polymers of polyglycolic acid,glycolide, lactic acid, lactide, dioxanone, trimethylene carbonate etc.,polyanhydrides, polyesteramides, polyortheoesters, polyphosphazenes, andcopolymers of these and related polymers or monomers, as well asnaturally derived polymers such as albumin, fibrin, collagen, elastin,chitosan, alginates, hyaluronic acid; and biosynthetic polyesters (e.g.,3-hydroxybutyrate polymers). However, like other biomaterials,bioabsorbable materials are also subjected to bacterial contaminationand can be a source of infections which are difficult to control. Thoseinfections quite often require their removal and costly antimicrobialtreatments.

Efforts to render bioabsorbable materials more infection resistantgenerally have focused on impregnating the materials with antibiotics orsalts such as silver salts, and have provided only limited andinstantaneous antimicrobial activity. It is desirable to have anantimicrobial effect which is sustained over time, such that theantimicrobial effect can be prolonged for the time that thebioabsorbable material is in place. This can range from hours or days,to weeks or even years.

Further, although antimicrobial/antibacterial metal coatings on medicaldevices have been suggested, metal coatings (such as silver or coppercoatings) have not been characterized or optimized. In suchapplications, it is important that the metal coatings do not shed orleave behind large metal particulates in the body, which may induceunwanted immune responses and/or toxic effects. Further, it is essentialthat the release of the antimicrobial agent (metal) be metered over thelifetime of the implant.

For example, U.S. Pat. No. 8,309,216 describes substrates includingdegradable polymers that include an electron donor layer (such assilver, copper or zinc) onto which particles of palladium and platinum,plus one other secondary metal (chosen from gold, ruthenium, rhodium,osmium, iridium, or platinum) are deposited onto. Although suchmaterials are described for anti-microbial implants (e.g., pacemakers,etc.), the separate layers formed by this method would be problematicfor antimicrobial coatings in which the undercoating of silver, copperor zinc were being released, potentially undermining the platinum andsecondary metal.

Similarly, U.S. Pat. No. 6,719,987 describes bioabsorbable materialshaving an antimicrobial metal (e.g., silver) coating that can be usedfor an implant. The silver coating is for release of particles(including ions) and must be in a crystalline form characterized bysufficient atomic disorder. In this example, the silver is alsodeposited in one or more layers. U.S. Pat. No. 6,080,490 also describesmedical devices with antimicrobial surfaces that are formed by layers ofmetals (e.g., silver and platinum) to release ions; layers are etched toexpose regions for release. The outer layer is always Palladium (and oneother metal), beneath which is the silver.

Thus, it would be highly desirable to provide devices, systems andmethods for the controlled release (particularly the controlled galvanicrelease) of a high level of silver, zinc or silver and zinc ions from abioabsorbable material into the tissue for a sufficient period of timeto treat or prevent infection.

Known systems and devices, including those described above, that haveattempted to use ions (e.g., silver and/or zinc) on bioabsorbablematerials to treat infection have suffered from problems such as:insufficient amounts of ions released (e.g., ion concentration was toolow to be effective); insufficient time for treatment (e.g., the levelsof ions in the body or body region were not sustained for a long enoughperiod of time); and insufficient region or volume of tissue in whichthe ion concentration was elevated (e.g., the therapeutic region was toosmall or limited, such as just on the surface of a device). Further, theuse of galvanic release has generally been avoided or limited because itmay effectively corrode the metals involved, and such corrosion isgenerally considered an undesirable process, particularly in a medicaldevice.

There is a need for antimicrobial coatings for substrates generally.Antimicrobial coatings may be useful for any surface that will beexposed to a conductive fluid, including blood, sweat, lymph, etc.,whether implanted or not. For example, there is a particular need forantimicrobial coatings for bioabsorbable materials, which can create aneffective and sustainable antimicrobial effect, which do not interferewith the bioabsorption of the bioabsorbable material, and which do notshed or leave behind large metal particulates in the body as thebioabsorbable material disappears.

Therapeutically, the level of silver and/or zinc ions released into abody is important, because it may determine how effective theantimicrobial ions are for treating or preventing infection. Asdescribed in greater detail below, the amount or ions releasedgalvanically may depend on a number of factors which have not previouslybeen well controlled. For example, galvanic release may be related tothe ratio of the anode to the cathode (and thus, the driving force) aswell as the level of oxygen available; given the galvanic reaction, thelevel of oxygen may be particularly important for at the cathode.Insufficient oxygen at the cathode may be rate-limiting for galvanicrelease.

For example, with respect to silver, it has been reported that aconcentration of 1 mg/liter of silver ions can kill common bacteria in asolution. Silver ions may be generated a galvanic system with silver asthe anode and platinum or other noble metal as the cathode. However oneof the challenges in designing a galvanic system for creation of silverion in the body that has not been adequately addressed is theappropriate ratios of the areas of the electrodes (e.g., anode tocathode areas) in order to create the germicidal level of free silverions. One challenge in designing a galvanic system is addressing theparasitic loss of current due to formation of silver chloride viareaction:AgCl+e→Ag+Cl(−) Eo=0.222 volts

We herein propose that it may be beneficial to have an area of thecathode under common biological condition that is at least larger than8% of the silver area to sustain the germicidal level of silver ions.For the purpose of this discussion, the following assumptions have beenmade: for a concentration of: [H+]=10^(−7) moles/liter; [OH−]=10^(−7)moles/liter; [O2]=5*10^(−3) moles/liter in the capillary; [Cl−]=0.1moles/liter. The values of the following were also assumed (as constantsor reasonable approximations): Faraday's constant, F=96000coulombs/mole; diffusivity of oxygen=0.000234 cm2/sec; diffusivity ofAg+=10^(−6) cm2/sec; diffusivity of Cl−=10^(−6) cm2/sec; R, Gasconstant=8.314 J K⁻¹ mol⁻¹; T, temp. K; Mw of silver=108 grams/mol;germicidal concentration of silver=10^(−5) mol/liter.

At equilibrium, for a galvanic cell it is acceptable to assume that thetwo electrodes are at the same potential. Using the Nernst equation, theequilibrium concentration of oxygen when the silver ion is at thegermicidal level may be calculated:E=Eo−(RT/nF)ln [(Activity of products)/(activity of reactants)]E=Eo−(0.0592/n) Log [(product)/(reactant)]

For the half cell reaction at the anode (silver electrode):Ag→Ag(+)+e(−). This reaction is written as a reduction reaction below:Ag(+)+e(−)→Ag Eo=0.800 volt eq.  (1)

[Ag+]=1 mg/liter*(gr/1000 mg)*(1 mol/108 (Mw of Ag))=10^(−5) Ag+mole/liter; E=0.800−(0.0592/1) log [1/(10^(−5)]. Based on this, theresulting E=8.00−(0.0592*5)=0.504 volt.

For the cathode, the reactions are:O₂+2H₂O+4e(−)→OH(−) Eo=0.401 volt eq.  (2)O₂+4H(+)+4e(−)→2H₂O Eo=1.229 volt eq.  (3)

In dilute aqueous solutions these two reactions are equivalent. Atequilibrium the potential for the two half-cell potentials must beequal:E=0.401−(0.0592/4) log {[OH(−)]^4/[O₂]}E(silver)=0.504=0.401−(0.0592/4) log {[10^−7]^4/[O2]}

Solving for [O₂], the result is: [O₂]=10^(−21) atm. The result of thisanalysis is that, thermodynamically speaking, as long as theconcentration of oxygen is above 10^(−21), the concentration of thesliver ion could remain at the presumed germicidal level.

However, a parasitic reaction to creation of silver ions is theformation of AgCl due to reaction of Cl− at the silver electrode. Thehalf-cell potential for this reaction is:AgCl+e(−)→Ag+Cl(−) Eo=0.222

Solving the Nernst equation for this reaction with E=0.504, theconcentration of chloride [Cl−]=2×10^(−5). The importance of thisreaction becomes apparent in evaluating the current needed to compensatefor the losses of current due to this reaction and the increased inratio of the area of the cathode to the anode.

The current density per until area requirements of the device can beestimated by combining Fick's and Faraday equations: the silver lossesdue to diffusion of silver from the device can be calculated using theFick's equation:j=D[C(d)−C(c)]/d  Fick's equation

The current needed to create the silver ions (A/cm2): i=j*n*F, where, jis the mass flux, C(d) is the concentration of the silver at the deviceand C(c) is concentration of silver at the capillary bed (=0). D is thediffusion coefficient of silver (10^(−6)) cm2/sec, d is the averagedistance of the device from the capillary bed (assumed to be=0.5 cm inthe bone), F is Faraday's constant (96000 col./mol), and n is the chargenumber.

The combination of the two equations for silver diffusion gives:i(Ag)=D*·n·F(C(d))/d

Thus:

$\begin{matrix}{{i({Ag})} = \left\{ {{10\hat{}\left( {- 6} \right)}*1*\left( {10\hat{}\left( {- 5} \right)} \right)*(96000)*} \right.} \\{\left. \mspace{85mu}{\left( {5*{10\hat{}\left( {- 3} \right)}} \right)/0.5} \right\}*\left( {1\mspace{14mu}{liter}\text{/}1000\mspace{14mu}{cc}} \right)} \\{\mspace{56mu}{= {2*{10\hat{}\left( {- 9} \right)}\mspace{14mu}{Amp}\text{/}{cm}^{2}}}}\end{matrix}$

The current needed to create the silver ions at the desiredconcentration is approximately 2 nanoAmp/cm². Similarly, the currentdensity (A/cm2) required to reduce the chloride ions from biologicallevel (0.1 molar) to the desired level of 2*10^(−5) molar could becalculated. For this equation the approximate values of the constantsare D=10^(−6), d=0.1 cm. The change in the Chloride concentration itassumed to be (0.1−2*10^(−5))=0.1. The current needed to feed theparasitic reaction can then be determined:

$\begin{matrix}{{i({cl})} = {\left\{ {\left( {10\hat{}\left( {- 6} \right)} \right)*(1)*(96000)*{(0.1)/(0.1)}} \right\}*\left( {1{lit}\text{/}1000\mspace{14mu}{cc}} \right)}} \\{= {9.6*{10\hat{}\left( {- 5} \right)}}} \\{= {96\mspace{14mu}{microAmp}\text{/}{Cm}^{2}}}\end{matrix}$

The total anodic current needed is: i(Ag)+i(Cl)=i(anodic)=96microAmps/cm². On the cathode, the reaction limitation is the flux ofoxygen form the source to the surface of the electrode. The maxi(cathodic) current could be approximated to:

$\begin{matrix}{{i\left( {O\; 2} \right)} = \left\{ {(0.000324)*(4)*(96000)*} \right.} \\{\left. {\left( {5*{10\hat{}\left( {- 3} \right)}} \right)/0.5} \right\}*\left( {1\mspace{14mu}{liter}\text{/}1000\mspace{14mu}{cc}} \right)} \\{\mspace{56mu}{= {1.24*{10\hat{}\left( {- 3} \right)}\mspace{14mu}{{Amp}s}\text{/}{cm}^{2}}}}\end{matrix}$

Since the total cathodic current must be equal to total Anodic current:i(cathodic)*Area of the cathode=i(anodic)*Area of Anode=>Area of theCathode/Area of the anode=(96*10^(−6)/(1.24*10^(−3))=0.077

This suggests that the area of the cathode must be at least equal to 8%of that of anode.

In addition to the ratio of the cathode to the ratio of the anode,another factor affecting the release of silver ions that has notpreviously been accounted for in galvanic release of silver to treatinfection is the concentration of oxygen needed.

The concentration of the oxygen needed to power the galvanic system istypically higher than that of the equilibrium concentration, since thesystem must overcome the activation energy of the reactions(over-potential) and supply the additional current. In the model belowwe evaluated the concentration of the oxygen needed to overcome theactivation energy for the reactions. Using the Tafel equation:η=β log [i/io]

where i=current density, η=the over-potential, β=overpotential voltageconstant, and io=intrinsic current density. For platinum, the oxygenover-potential constants are: β=0.05 volt and io=10^(−9) A/m². Usingi=9.6*10^(−5) Amp then:η=0.05 log [9.6*10^(−5)/(10^(−9))]η=0.25 volt

Adding the over potential to the potential at the equilibrium (0.501volts), and the total working half-potential needed at the cathodebecomes equal to (0.501+0.25)=0.751.

Using the Nernst equation to determine the concentration of oxygen atthe cathode:E=0.751=0.401−(0.0592/4) log {[OH(−)]^4/[O2]}

Thus, the concentration of oxygen at the electrode should be at least7*10^ (−5) mole.

The results of this analysis show that an implanted galvanic systemwould benefit from having an area of the cathode to the area of theanode (A_(cathode)/A_(anode)) of greater that about 8% and theconcentration of the oxygen at the site of implant to be at least7*10^(−5) moles per liter, which may avoid rate-limiting effect.

Thus, to address the problems and deficiencies in the prior artmentioned above, described herein are systems, methods and devices (andin particular coatings, methods of coatings) for substrates thatcontrollably release antimicrobial metal ions, including apparatuses(e.g., devices and/or systems) and methods for prevent infection and foreliminating existing infections. The coatings described herein may beused as part of any appropriate substrate, including medical devices(both implanted, inserted, and non-implanted/inserted medical devices),and non-medical devices including hand-held articles. In some particularexamples, described below are implants including bioabsorbablesubstrates, and methods for using them.

SUMMARY OF THE DISCLOSURE

In general, described herein are coatings and methods of forming andusing coatings for any substrate that will come into contact with abodily fluid and/or secretion, in which the coating may galvanicallyrelease antimicrobial ions. The coatings are configured so that therelease of the antimicrobial ions (e.g., silver, zinc and/or copper) issustained over a predetermined time period of continuous or intermittentexposure to the bodily fluid, and further so that the amount and/orconcentration of the antimicrobial ions released is above apredetermined threshold for effective antimicrobial effect eitherlocally or within a region exposed to the coating.

Although particular attention and examples of types of substrates, suchas medical devices, and in particular implantable medical deviceincluding bioabsorbable substrates, it should be readily understood thatthe coatings described herein may be used on any substrate surface thatwill come into contact with bodily fluids which would benefit from anantimicrobial effect, including devices that are not inserted orimplanted into a body. Bodily fluids are generally electricallyconductive, and may include any of: blood, blood serum, amniotic fluid,aqueous humor, vitreous humor, bile, breast milk, cerebrospinal fluid,cerumen, chyle, chyme, endolymph, perilymph, exudates, feces (diarrhea),female ejaculate, gastric acid, gastric juice, lymph, mucus (includingnasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleuralfluid, pus, rheum, saliva, sebum, semen, sputum, synovial fluid, sweat,tears, urine, vaginal secretion, vomit, etc.

As used herein, a substrate may be any surface onto which the coatingmay be applied, which may be any appropriate material, including, butnot limited to metals (e.g., alloys, etc.), ceramics, stone, polymers,wood, glass, etc., including combinations of materials. In somevariations the surface of the substrate may be prepared before thecoating is applied, as described herein. The substrate may be rigid orflexible. In particular, the coatings described herein may be applied toflexible and/or fiber-like materials such as strings, sutures, wovenmaterials, thin electrical leads, and the like. As described in greaterdetail herein, the coating typically does not inhibit the flexibility,pliability, bendability, etc. of the substrate material.

The coatings described herein typically include co-depositions of ananodic metal (e.g., one or more of zinc, silver, and/or copper) and acathodic metal (e.g., one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium and rhenium). The anodicand cathodic material in the coating are non-uniformly dispersed withinthe coating, so that there are veins (e.g., microdomains ormicroregions, such as clusters, clumps, etc.) of anodic metal within amatrix of cathodic metal and/or veins of cathodic metal within a matrixof anodic metal. The relative amounts of anodic metal in the coating maybe between 20% and 80% by volume, or more preferably between 25% and 75%by volume, or more preferably still, between 30% and 70% by volume(e.g., greater than 20%, greater than 25%, greater than 30%, etc.).

The anodic metal within the coating typically forms a continuous paththrough the coating (extending from the outer surface of the coating allthe way to the base of the coating, which may be the portion against thesubstrate), so that all or most all (e.g., greater than 80%, greaterthan 85%, greater than 90%, greater than 95%, greater than 96%, greaterthan 97%, greater than 98%, greater than 99%, etc.) of the anodic metalin the coating is interconnected, preventing entrapment of a substantialportion of the anodic metal within the coating. Similarly, the cathodicmetal within the coating may be in continuous contact throughout thecoating layer (extending from the outer surface of the coating all theway to the base of the coating, which may be the portion against thesubstrate) so that all or most all (e.g., greater than 80%, greater than85%, greater than 90%, greater than 95%, greater than 96%, greater than97%, greater than 98%, greater than 99%, etc.) of the cathodic metal inthe coating is interconnected.

As mentioned, the coatings described herein may be applied to anyappropriate substrate. For example, an apparatus that galvanicallyreleases antimicrobial ions may include: a substrate; and a coating onthe substrate comprising an anodic metal (that has been co-depositedwith a cathodic metal on the substrate) to form a non-uniform mixture ofthe anodic and cathodic metals, wherein the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal within the matrix of cathodic metal or a continuous path ofinterconnected veins of cathodic metal within the matrix of anodicmetal, wherein the continuous path extends from an outer surface of thecoating to the substrate; further wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isinserted into a subject's body.

The substrate may be an implant configured to be inserted into a humanbody, including a medical device. The substrate may be device configuredto be temporarily or permanently inserted into the body (e.g., surgicaltools, implants, etc.). In some variations the substrate may be a deviceconfigured to be worn on a human body (e.g., jewelry, clothing, surgicalgowns, masks, gloves, etc.). The substrate may be a structure configuredto hold, support and/or house a subject (e.g., gurney, chair, bed,etc.). The coating may be applied to all or a portion of the substrate,particularly those surfaces of the substrate that may be placed incontact with a bodily fluid (e.g., a handle, supporting surface, etc.).The substrate may be a household item, such as a cutlery (e.g., spoons,baby spoons, forks, etc.), food handling items (e.g., platters, plates,straws, cups, etc.), handles (e.g., doorknobs, pushes, etc.), faucets,drains, tubs, toilets, toilet knobs, light switches, etc.

The anodic metal may be any combination of the anodic metals describedherein (e.g., zinc, silver, copper, both zinc and silver, etc.). Theanodic metal may be least about 30 percent by volume (or in somevariations, by weight, e.g., when the densities of anodic and cathodicmaterials are similar) of the coating.

The cathodic metal may generally have a higher galvanic potential thanthe anodic metal. This may drive the galvanic (e.g., “corrosion”) of theanodic metal when the coating is exposed to a bodily fluid. For example,the cathodic metal may comprise one or more of: palladium, platinum,gold, molybdenum, titanium, iridium, osmium, niobium and rhenium.

The coating may be formed by vapor deposition. For example, the anodicmetal and the cathodic metal may have been vapor-deposited onto thesubstrate so that the anodic metal is not encapsulated by the cathodicmetal, e.g., so that the anodic metal (and/or in some variations thecathodic metal) include veins that extend continuously through thecoating from the outer surface to the base (e.g., the “bottom” of thecoating adjacent to the substrate) of the coating. Thus, the continuouspath of interconnected veins may be interconnected so that less than 15%of the anodic metal is completely encapsulated within the matrix ofcathodic metal, or less than 15% of the cathodic metal is completelyencapsulated within the matrix of anodic metal. The continuous path ofinterconnected veins may be interconnected so that less than 10% of theanodic metal is completely encapsulated within the matrix of cathodicmetal, or less than 10% of the cathodic metal is completely encapsulatedwithin the matrix of anodic metal.

An apparatus that galvanically releases antimicrobial ions may include:a substrate; and a coating on the substrate comprising zinc and silverand a cathodic metal that are all co-deposited onto the substrate,wherein the zinc and silver are at least about 25 percent by volume (orin some variations by weight) of the coating and form a non-uniformmixture of the zinc and the cathodic metal and a non-uniform mixture ofthe silver and the cathodic metal, wherein the coating comprises aplurality of microregions or microdomains of zinc and silver in a matrixof cathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of zinc and a matrix of silver, themicroregions or microdomains forming a continuous path of interconnectedveins of zinc and silver within the matrix of cathodic metal or acontinuous path of interconnected veins of cathodic metal within thematrix of zinc and the matrix of silver, wherein the continuous pathsextend from an outer surface of the substrate; further wherein the zincand silver are galvanically released as antimicrobial ions when theapparatus is inserted into a subject's body.

In some variations, the substrate may be bio-absorbable. For example, insome variations, the substrate is configured to degrade within the bodyto form a degradation product including an anion that complexes withions of the anodic metal and diffuses into the subject's body to form anantimicrobial zone. For example, a bioabsorbable apparatus thatgalvanically releases antimicrobial ions may include: an implant havingan outer surface comprising a substrate; and a coating on the substratecomprising an anodic metal that is co-deposited with a cathodic metal onthe substrate to form a non-uniform mixture of the anodic and cathodicmetals, wherein the coating comprises a plurality of microregions ormicrodomains of anodic metal in a matrix of cathodic metal or aplurality of microregions or microdomains of cathodic metal in a matrixof anodic metal, the microregions or microdomains forming continuouspaths of interconnected veins of anodic metal within the matrix ofcathodic metal or continuous paths of interconnected veins of cathodicmetal within the matrix of anodic metal, wherein the continuous pathsextend from an outer surface of the coating to the substrate; furtherwherein the anodic metal is galvanically released as antimicrobial ionswhen the apparatus is inserted into a subject's body.

Thus, also described herein are bioabsorbable substrates, andparticularly bioabsorbable filaments, that galvanically releaseantimicrobial ions. The bioabsorbable filament is coated with an anodicmetal (such as silver, copper and/or zinc) that has been co-depositedwith a cathodic metal (such as platinum, gold, palladium) along at leasta portion of the length of the filament. The filament retains itsflexibility. After insertion into the body, the anodic metal corrodes asthe filament is bioabsorbed. The degradation of the filament may createa local pH that enhances the release of the silver and/or copper and/orzinc ions.

In general, the coated filaments may be arranged into structures (e.g.,sutures, mesh, slings, yarns, etc.) that can be implanted into the body.

As mentioned, the anodic and cathodic metals forming the coatingsdescribed herein are typically co-deposited together, and not coated inlayers (e.g., atop each other). For example, the metals may be jointlyvapor deposited. Examples of jointly deposited anodic and cathodicmaterials include silver-platinum, copper-platinum, zinc-platinum,silver-gold, copper-gold, zinc-gold, etc. Different types of jointlydeposited anodic and cathodic metals may be arranged on the bioabsorblesubstrate. For example, silver-platinum may be coated near (either nottouching or touching) a region of zinc-platinum; different co-depositedanodic/cathodic metals may be a spacer region on the substrate.

In some variations, described herein are devices and methods forpreventing an infection in an implantable device such as a pacemaker ora defibrillator when inserting it into a body by incorporatingbioabsorbable materials that galvanically releaseantimicrobial/antibacterial metals such as silver and/or zinc and/orcopper. For example, an implant may be inserted into a woven mesh madeof a bioabsorbable material that is coated (or impregnated) with ananti-microbial anodic metal ions such as silver or zinc co-depositedwith a catalytic cathodic metal such as platinum, gold, or palladium.

In general, as mentioned above, the anodic metal may be silver, zinc, orany other metal with germicidal activity, and the cathode metal may beplatinum, gold, palladium, or any other metal with catalytic action,including molybdenum, titanium, iridium, osmium, niobium and rhenium.The biodegradable substrate may be a biodegradable filament, such aspolylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA),polyglycolide (PGA), polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL). As used herein the terms biodegradable andbioabsorbable may be used interchangeably.

For example, described herein are biodegradable filaments that may beformed into an envelope, pouch, pocket, etc. (generically, aco-implantable structure) made of a biodegradable polymer (such as PLGA,PGA, PLA, polycaprolactone, etc.). The implant may be co-implanted withthe co-implantable structure, for example, by placing the mesh onto theimplant before, during or after insertion into the body. Theco-deposited metal coating of the co-implantable structure creates agalvanic system resulting in release of germicidal ions protecting thedevice from getting infected in the body once the device is implantedwith the structure into a body. In the semi-aqueous environment of thebody, the metal will corrode over time by releasing the ions (e.g.,silver ions, copper ions, zinc ions, etc.). A coated bioabsorbablepolymer could also or alternatively be used as an insert inside thelumen of the device such as a cannula, cannulated screw, or as a coatingon a device. In another configuration the metal ions could be coupledwith a poly-anionic (negatively charged) polymer and mixed with thepolymer.

For example, described herein are bioabsorbable apparatuses thatgalvanically release antimicrobial ions. The apparatus may comprise: aflexible length of bioabsorbable filament; and a coating on the lengthof filament comprising an anodic metal that is co-deposited with acathodic metal on the length of filament; wherein the coated filament isflexible; further wherein the anodic metal is galvanically released asantimicrobial ions when the apparatus is inserted into a subject's body.

In general, in apparatuses (systems and devices) in which the anodicmetal and the cathodic metal are co-deposited (e.g., by vapordeposition) the anodic metal may be at least about 25 percent (e.g., atleast about 30 percent, at least about 35 percent, etc.) by volume ofthe coating. This may prevent complete encapsulation of the anodicmaterial (e.g., zinc, silver, etc.) by the cathodic material (e.g.,palladium, platinum, gold, molybdenum, titanium, iridium, osmium,niobium and rhenium). As described in greater detail below, the coatingsapplied may be configured to result in microregions or microdomains ofanodic material in a matrix of cathodic material. The microdomains maybe interconnected or networked, or they may be isolated from each other.In general, however, the concentrations of anodic material and cathodicmaterial may be chosen (e.g., greater than 25% by volume of the anodicmaterial, between about 20% and about 80%, between about 25% and about75%, between about 30% and about 70%, etc.) so that the majority of theanodic material in the coating thickness is connected to an outersurface of the coating, allowing eventual corrosion of most, if not allof the anodic metal as anti-bacterial metal ions, while providingsufficient cathodic material to provide adequate driving force for thecorrosion of the anodic material. Thus, the coating may comprise theanodic metal and the cathodic metal that have been vapor-deposited ontothe length of filament so that the anodic metal is not encapsulated bythe cathodic metal.

As mentioned, the anodic metal may comprise zinc, copper or silver, orin some variations both zinc and silver. In general, the cathodic metalhas a higher galvanic potential than the anode. For example, thecathodic metal may be one or more of: palladium, platinum, gold,molybdenum, titanium, iridium, osmium, niobium and rhenium.

As mentioned, in general the bioabsorbable substrate (e.g., filament)may comprise one or more of: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL).

In general, the bioabsorbable substrate (including a length ofbioabsorbable filament) is configured to degrade within the body to forma degradation product, including an anion that complexes with ions ofthe anodic metal and diffuses into the subject's body to form anantimicrobial zone.

The bioabsorbable substrate (e.g., bioabsorbable filament) may beconfigured as a mesh, bag, envelope, pouch, net, or the like, that maybe configured to hold an implant. For example, the flexible structuremay be configured to at least partially house a pacemaker,defibrillator, neurostimulator, or ophthalmic implant.

Also described herein are bioabsorbable apparatuses that galvanicallyrelease antimicrobial ions and comprise: a plurality of lengths ofbioabsorbable filament arranged in a woven structure; and a coating onthe lengths of filament comprising zinc and silver and a cathodic metalthat are all co-deposited onto the lengths of filament, wherein the zincand silver are at least about 25 percent by volume of the coating;further wherein the zinc and silver are galvanically released asantimicrobial ions when the apparatus is inserted into a subject's body.As mentioned, the woven structure may form a mesh, bag, envelope, pouch,net, or other structure that is configured to at least partially enclosean implant within the subject's body.

Also described herein are bioabsorbable apparatuses that galvanicallyreleases antimicrobial ions and include: a plurality of lengths ofbioabsorbable filament; and a coating on the lengths of filamentcomprising an anodic metal that is co-deposited with a cathodic metal onthe lengths of filament; wherein the lengths of filament are arrangedinto a flexible structure; further wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isinserted into a subject's body.

Methods of forming any of these apparatuses are also described,including methods of forming a coated bioabsorbable substrate, forexample, by co-depositing (vapor depositing) an anodic material and acathodic material onto the substrate. The substrate may be a fiber orthe structure formed of the fiber. In some variations the method mayalso include forming different regions of co-deposited anodic andcathodic materials, wherein the different regions include differentcombinations of anodic and cathodic materials. The different regions maybe non-contacting. In general, co-deposing anodic and cathodic materialsare typically performed so that the anodic material forms greater than25% by volume of the coating, preventing encapsulation of the anodicmaterial by cathodic material within the coating.

Also described are methods of treating a subject using the bioabsorbablematerials that are co-deposited with one or more coating of anodic andcathodic metals (e.g., materials). For example, described herein aremethods of galvanically releasing antimicrobial ions to form anantimicrobial zone around an implant that is inserted into a subject'stissue. The method may include step of: inserting into the subject'stissue an apparatus comprising a plurality of lengths of bioabsorbablefilament having a coating comprising an anodic metal and a cathodicmetal that are co-deposited onto the lengths of filament, wherein theimplant is at least partially housed within the apparatus; galvanicallyreleasing antimicrobial ions from the coating (e.g., galvanicallyreleasing ions of silver and zinc); allowing the lengths of filament todegrade into a degradation product including anions, wherein the anionscomplex with antimicrobial ions of the anodic metal and diffuse into thetissue to form an antimicrobial zone around the implant. The method mayalso include inserting an implant into the apparatus before theapparatus is inserted into the subject's body. For example, insertingthe apparatus into the body may comprise inserting a flexible apparatuscomprising the plurality of length of bioabsorbable filaments forming abag, envelope, pouch, net or other structure (woven or otherwise) formedto hold the implant. For example, the method may also include insertinga pacemaker, a defibrillator or a neurostimulator into the apparatus.

Inserting the apparatus may comprise inserting the apparatus having aplurality of lengths of bioabsorbable filaments coated with the anodicmetal that comprises silver and zinc that are co-deposited onto thelengths of filament with the cathodic metal.

Allowing the lengths of filament to degrade may comprise degrading thelengths of filament into anions that bind to silver ions from thecoating. For example, inserting the apparatus comprises inserting theapparatus having a plurality of lengths of bioabsorbable filamentscoated with the anodic metal that is co-deposited onto the lengths offilament with the cathodic metal, wherein the anodic metal is at leastabout 25 percent by volume of the coating (e.g., at least about 30%, atleast about 35%, etc.).

Inserting the apparatus comprising the plurality of lengths ofbioabsorbable filament may comprise inserting the apparatus having aplurality of lengths of one or more of: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), and polyglycolide (PGA).

In general, the antimicrobial zone around the implant may be sustainedfor at least seven days.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIGS. 1A-1F illustrate the general concept of galvanic release of silverions.

FIG. 2A shows a cross-sectional view through one example of a substratehaving a combined coating, comprising an anodic metal that isco-deposited with a cathodic metal.

FIG. 2B is a schematic representation of an enlarged view of a portionof the coated substrate of FIG. 2A, schematically illustratingmicro-domains or veins of anodic metal (not to scale) within a cathodicmatrix.

FIG. 2C is another schematic representation of an enlarged view of aportion of the coated substrate of FIG. 2A.

FIG. 2D is an example of the galvanic release (and corrosion) of acoating on a substrate such as the one shown in FIG. 2A.

FIGS. 3A-3C illustrate top views of alternative variations of coatingpatterns for different combined coatings, such as silver/platinum andzinc/platinum.

FIG. 4 is an example of a bioabsorbable pouch woven from one or morestrands, wherein the strands of the pouch are coated with the combinedcoatings described herein for release of antimicrobial ions.

FIG. 5A illustrates a fiber or filament (e.g., suture fiber) coated witha striped pattern of a combined coating for galvanic release of metalions.

FIG. 5B illustrates a portion of a barbed suture fiber coated asdescribed herein.

FIG. 5C is a portion of a suture fiber that is coated as describedherein.

FIG. 5D is an example of a needle and suture (shown as a combined needlepreloaded with suture) in which both needle and suture are coated asdescribed herein.

FIG. 6 is an example of a length of suture formed from a bioabsorbablesubstrate onto which a combined coating has been regionally applied(e.g., near the distal end).

FIG. 7 illustrates one example of a medical device configured as atransvaginal mesh having a combined coating for release of metal ionsafter insertion into the body.

FIG. 8A is a side perspective view of one example of a plug or patchthat may be used, e.g., to repair a hernia. The device is coated withmultiple types of combined coatings for galvanic release of metal ions.

FIG. 8B shows an enlarged view of one region of the plug.

FIG. 9 is a perspective view of one variation of a bandage or patchincluding a combined coating, shown on a patient's knee.

FIG. 10 illustrates one variation of an artificial dura (mesh) includinga combined coating for galvanic release of metal ions.

FIG. 11 shows an example of a material that may be used as within awound or surgical site to prevent or treat infection. The material maybe a porous and/or bioabsorbable mesh that is configured to galvanicallyrelease metal ions.

FIGS. 12A and 12B show side perspective and end views, respectively ofone variation of a cannula including a pattern of a combined coating forthe release of antimicrobial metal ions.

FIGS. 13A and 13B illustrate one example of a medical device (animplantable pacemaker) that may be used with the co-deposited galvaniccoatings described herein.

FIG. 13C is a schematic depiction of a conventional cardiac stimulationand defibrillation arrangement.

FIGS. 14A and 14B illustrate another example of a medical device (avenous catheter) that may be coated with the co-deposited galvaniccoatings described herein.

FIGS. 15A and 15B show an example of a catheter (including a cuff) thatmay include a galvanically released antimicrobial coating that isco-deposited as described herein. FIG. 15A is an example of a triplelumen device and FIG. 15B is an example of a dual lumen device.

FIG. 16 shows one example of a catheter that has been coated byco-deposition of the galvanic coating described herein.

FIG. 17A shows a cannulated bone screw that may be used with a coatedinsert as shown in FIG. 17B. The coated insert may be a bioabsorbablemesh, coated as described herein.

FIG. 17C shows the bone screw of FIG. 17A with the mesh of FIG. 17Binserted.

FIG. 18A shows a bone screw coated as described herein.

FIG. 18B shows a bone screw similar to that shown in FIG. 18A, but whichhas been coated in a striped pattern (e.g., having regions that areeither uncoated, or coated with different anionic materials/combinationsof materials, as described in FIGS. 3A-3C, above.

FIG. 19A is another example of bone screw implant having openings orchannels from which members (shown extending in FIG. 19B) may extend.Either or both the bone screw and the extending members may be coated asdescribed herein.

FIG. 20 shows an example of an animal cage coated as described herein.

FIG. 21 shows an example of a doorknob coated as described herein.

FIG. 22A shows an example of cutlery (a fork and spoon) coated asdescribed herein. FIG. 22B shows another example of spoon coated asdescribed herein.

FIG. 23A show a cross-sectional view through an example of a substratesurface having a coating comprising an anodic metal co-deposited with acathodic metal, in which the coating has been cracked, enhancingavailable surface area, as described herein.

FIG. 23B is a schematic representation of an enlarged view of a portionof the coated substrate of FIG. 23A, schematically showing (not toscale) micro-domains or veins of anodic metal within a cathodic matrix,showing cracks in the coating.

DETAILED DESCRIPTION

In general, described herein are apparatuses (e.g., systems and devices)that include a coating or layer that galvanically releases antimicrobialions over an extended period of time. The coating may be applied to asubstrate, e.g., a bioabsorbable and/or biodegradable substrate that maydegrade during the same period that the antimicrobial ions are beingreleased, e.g., days, months, years. In some variations the substratemay be coated with an adhesion layer on the substrate. The substrate maybe pre-treated (e.g., to remove oxides, such as the titanium oxide layeron a nickel titanium substrate). In general, the coating may include acombination of anodic metal, such as silver and/or zinc and/or copper,and a cathodic metal, such as palladium, platinum, gold, molybdenum,titanium, iridium, osmium, niobium and rhenium, where the anodic metaland cathodic metals are co-deposited (e.g., by vapor deposition) so thatthe anodic metal is exposed to an outer surface of the coating and notfully encapsulated in the cathodic metal, and there is sufficientcathodic metal to drive the galvanic release of anodic ions when exposedto bodily fluids such as blood, lymph, etc. (e.g., when implanted intothe body).

For example, described herein are apparatuses including substrates ontowhich anodic metal and cathodic metals are co-deposited to form acoating, allowing the anodic metal to be galvanically released as ions(e.g., antimicrobial silver, copper and/or zinc ions) when the apparatusis exposed to a conductive fluid (e.g., a bodily fluid). The substratemay include an adhesive coating (such as a tantalum or titanium layerthat is applied before the galvanic coating of co-deposited antic andcathodic metal).

Galvanically Releasable Coating

In general, the antimicrobial metal ion coatings described herein aregalvanically releasable within a tissue, and include one or more anodicmetal (typically silver and/or zinc and/or copper) that is co-depositedwith a cathodic metal (typically platinum and/or palladium). The anodicmetal and the cathodic metal are co-deposited, e.g., by sputtering orother appropriate methods described herein, so that the resultingcoating is non-homogenous, with a percentage of anodic metal (e.g.,silver) that is greater than about 30% co-distributed (typically inclusters, veins or clumps as illustrated and described below) with thecathodic metal (e.g., platinum), where the cathodic metal is greaterthan about 30% (e.g. % w/w) of the coating. The antimicrobial metal ioncoatings described herein may be generally referred to as non-homogenousmixtures where the anode is distributed in connected clusters (veins)within the cathodic metal (or vice-versa). Generally, both the anodicmetal and the cathodic metal are exposed in microdomains across theouter surface of the coatings, allowing galvanic release; as the anodicmetal is released, it may form channels (e.g., tunnels, mines, etc.)through the coating, e.g., within the cathodic material. In somevariations the cathodic material remains behind. In some variations someof the cathodic material may also be released.

Thus, in any of these variations, the coating may comprise a non-uniformmixture of the anodic and cathodic metals, with a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal, and/or a plurality of microregions or microdomains of cathodicmetal in a matrix of anodic metal. These microregions or microdomainsmay be formed by co-deposition as described herein.

Any of the coatings described herein may include co-deposited multipleanodic and/or multiple cathodic metals forming the coating. In somevariations, it may be preferable to separate regions having a firstanodic metal (e.g., silver) from regions having a second anodic metal(e.g., zinc), so that they are separated (e.g., in some variationselectrically separated) and/or non-contacting, allowing preferentialrelease of one metal ion (e.g., zinc) compared to silver. This may allowcontrol of the release profile, and may extend the length of effectiverelease time for as coating.

In general, these coatings may be any appropriate thickness. Forexample, the thickness could be a few microns thick or more (e.g.,greater than 2 microns, greater than 5 microns, greater than 10 microns,greater than 15 microns), etc. For example, the thickness of the coatingmay be between about 10 microinches (approximately 2500 Angstroms orapproximately 0.25 microns) and about 25 microinches (approximately 6350Angstroms or about 0.64 microns). The thickness of the coating may beuniform or non-uniform. Only some regions of the substrate may becoated, while other regions may be masked to prevent coating. Forexample, in an electrical stimulation apparatus (e.g., cardiacstimulator, neurostimulator, etc.) the body and/or connectors of thedevice may be insulated while the electrical leads (electrical contacts)to deliver energy to the tissue may be uncoated. Alternatively in somevariations the electrical contacts are coated as described herein.

FIGS. 1A-1F conceptually describe a simple galvanic cell setup such asfor use in a body. The setup is shown treating an infection, but thesame process could be applied to healthy tissue to prevent an infection(prophylactically). The components including a first metal 2 (e.g.,silver), second metal 4 (e.g., platinum), and electrolytic fluid 6(e.g., blood) are shown individually in FIGS. 1A-1C and arranged in atissue in FIGS. 1D-1F. Electrolytic body fluid 6 is shown bathing orcontacting healthy tissue 10 as well as infected tissue 8. When silvermetal 2 contacts platinum metal 4 in body fluid 6, it forms a galvaniccell with a silver anode and platinum cathode. As shown in FIG. 1E,ionic silver 12 is generated and spreads through the body fluid, killingmicroorganisms and creating an infection-free zone 14 in body fluid 16in the vicinity of the anode. After treatment is complete, the silveranode 2 may be completely corroded 20 leaving an infection-free bodyfluid 18. Any metal with a higher redox potential than silver may beused as the cathode. The metal may be a noble metal, such as gold,palladium or platinum. Although the example shown in FIGS. 1A-1Fdescribes using a silver metal anode that is placed adjacent to aplatinum metal cathode, described herein are coatings in which theanodic metal (e.g., silver, zinc, copper) is co-deposited onto abiodegradable substrate.

In general, a coating of anodic metal and cathodic metal may beconfigured so that the anodic metal and cathodic metal are within thesame coating layer. The microregions of anodic metal may be embeddedwithin the cathodic metal, including being embedded within a matrix ofcathodic metal (or vice versa). As illustrated below, the microdomainsor microregions of anodic metal are within a cathodic matrix, allowing alarge spatial release pattern of anodic metal ions by galvanic actiontriggered by the contact of the anodic metal and the cathodic metalwithin the electrolytic bodily fluid. The coatings described herein, inwhich the anodic metal and the cathodic metal are combined as part ofthe same layer may be referred to as “combined” coatings, in which ananionic metal and a cationic metal are both jointly coated, and/ornon-homogenous (non-uniform) mixtures of anodic and cathodic metal.

The combined coatings described herein may be non-uniform mixtures ofanodic and cathodic metals. For example, the anionic metal may formmicroregions or microdomains within the cationic metal (or vice versa).In general, the cathodic metal microdomains may form one or more(typically a plurality) of continuous paths through the cathodic metal.For example, the microdomains described herein may be veins, clusters,threads, clumps, particles, etc. (including interconnected veins,clusters, threads, clumps, particles, etc.) of anodic metal, e.g.,silver, copper, and/or zinc, etc., that are connected to an outersurface of the coating, so that they are exposed to the electrolyticbodily fluid (e.g., blood). The microdomains of anodic metal may form anetwork within the matrix of the cathodic metal. Thus, the anodic metalsmay be present in one or more networks that are electrically connectedwithin the cathodic matrix. The individual sizes of particles, threads,branches, veins, etc. forming the microdomains may be small (typicallyhaving a length and/or diameter, e.g., less than a 1 mm, less than 0.1mm, less than 0.05, less than 0.01 mm, less than 0.001 mm, less than0.0001 mm, less than 0.00001 mm, etc.). Similarly, in some variationsthe matrix may be the anodic metal and the cathodic metal may bereferred to as forming microdomains (e.g., where the percentage ofcathodic metal in the coating is less than 50%, less than 45%, less than40%, less than 30%, etc. by volume of the coating).

A combined anodic metal and cathodic metal forming a combined coating(or a portion of a coating) may be formed of a single anodic metal(e.g., silver) with a single cathodic metal (e.g., platinum), which maybe referred to by the combined anodic metal and cathodic metals formingthe coating or portion of a coating (e.g., as a combined silver/platinumcoating, a combined silver/palladium coating, a combined zinc/platinumcoating, a combined zinc/palladium coating, etc.). In some variations acombined coating may include multiple anodic and/or cathodic metals. Forexample, the combined coating may include zinc and silver co-depositedwith platinum.

As mentioned, the anodic metal in the combined coating may include acontinuous path connecting the anodic metal to an exposed outer surfaceof the coating so that they can be galvanically released from thecoating. Deeper regions (veins, clusters, etc.) of the anodic metal maybe connected to more superficial regions so that as the more superficialregions are corroded away by the release of the anodic ions, the deeperregions are exposed, allowing further release. This may also exposeadditional cathodic metal. Thus, in general, anodic metal microdomainsare not completely encapsulated within the catholic metal. In somevariations, the majority of the anodic metal is not completelyencapsulated within the cathodic metal, but is connected to an exposedsite on the surface of the coating via connection through a moresuperficial region of anodic metal; although some of the anodic metalmay be completely encapsulated. For example, the coating may include ananodic metal in which less than 50 percent of the total anodic metal iscompletely encapsulated within the cathodic metal (e.g., less than 40%,less than 35%, less than 30%, less than 25%, less than 20%, less than15%, less than 10%, etc.).

The co-deposited anodic and cathodic combined coatings described hereinfor the galvanic release of anodic ions may be formed by co-depositingthe anodic metal and the cathodic metal so as to minimize the amount ofencapsulation by the cathodic material. For example, the percentage ofthe anodic material may be chosen so that there is both an optimalamount of cathodic metal to drive reasonable galvanic release in thepresence of an electrolyte, and so that there is sufficient continuityof anodic metal with the combined coating to form a continuous path toan exposed surface of the coating, making it available for galvanicrelease. For example, a coating may be formed by co-depositing theanodic metal and the cathodic metal (e.g., sputtering, vapor deposition,electroplating, etc.) where the concentration of the anodic metal ishigh enough to allow the formation of a sufficient number of continuouspaths through the thickness of the coating. We have found that acombined coating in which more than 25% by volume (or more preferablymore than 30%) of the coating is formed of the anodic metal issufficient to form a combined coating with a cathodic metal in whichmore than half (e.g., >50%) of the anodic metal is connected by acontinuous path to the surface of the coating, permitting galvanicrelease. For example, a coating having between about 33-67% of anodicmetal and between about 67-33% of cathodic metal may be preferred. Atthese percentages, less than half of the anodic metal is fullyencapsulated by the non-corroding cathodic metal and trapped within thecoating. Thus, in general, the combined coatings (also referred to asco-deposited coatings) may include more than 25% (e.g., 30% or greater,35% or greater) by volume of anodic metal that is co-deposited with thecathodic metal. In some variations, the remainder of the coating (e.g.,between 5% and 75%) may be cathodic metal. Thus, the percent of anodicmetal co-deposited with cathodic metal may be between 25%-95% (e.g.,between about 30% and about 95%, between about 30% and about 90%,between about 30% and about 80%, between about 30% and about 70%,between about 25% and 75%, between about 25% and 80%, between about 25%and 85%, between about 25% and 90%, between about 35% and 95%, betweenabout 35% and 90%, between about 35% and 85%, between about 35% and 80%,between about 35% and 75%, between about 35% and 70%, between about 35%and 65%, etc.), with the remainder of the coating being cathodic metal.Further, the coating (or at least the outer layer of the coating) may beprimarily (e.g., >95%) formed of anodic and cathodic metals distributedin the micro-domains as described herein. In some variations the coatingmay also include one or more additional materials (e.g., a metal,polymer, or the like). The additional material(s) may be inert (e.g.,not participating in the galvanic reaction between the anodic metal andthe cathodic metal), or it may be electrically conductive. For example,the additional material may be co-deposited with the anodic and cathodicmetals, and may also be distributed in a non-homogenous manner.

For example, a mixed coating may be formed using a PVD-system.Vaporization of metal components may be performed on a substrate (withor without an adhesive layer), e.g., using an arc and/or a magnetronsputter from metallic targets. Mixed coatings may be produced bysimultaneous vaporization of both metals while the substrate is heldfixed, or is moved (e.g., rotated). After coating, the coated materialsmay be cleaned, e.g., using an argon plasma and/or other methods.

As mentioned, any of the coatings described herein may be of anyappropriate thickness. For example, the coatings may be between about500 microinches and about 0.01 microinches thick, or less than about 200microinches (e.g., between about 10 microinches and about 500microinches), less than about 150 microinches, less than about 100microinches, less than about 50 microinches, etc. The thickness may beselected based on the amount and duration (and/or timing) of the releaseof anodic metal. In addition, the coatings may be patterned, e.g., sothat they are applied onto a substrate in a desired pattern, or over theentire substrate. As mentioned and described further below, differentcombined coatings may be applied to the same substrate. For example, acombined coating of silver/platinum may be applied adjacent to acombined coating of zinc/platinum, etc. The different combined coatingsmay have different properties (e.g., different anodic metal, differentanodic/cathodic metal percentages, different thicknesses, etc.) andtherefore different release profiles. Combinations in which differentcombined coatings are in (electrical) contact with each other may alsohave a different release profile than combinations in which thedifferent coatings are not in electrical contact. For example, amaterial may include a first combined coating of zinc and a cathodicmetal (e.g., zinc/platinum) and a second combined coating of silver anda cathodic metal (e.g., silver/platinum). If the first and secondcombined coatings are in electrical contact, the zinc will begalvanically released first. If the first and second combined coatingsare not in electrical contact, then both zinc and silver will beconcurrently released (though zinc may be released more quickly and mydiffuse further).

For example, FIG. 2A illustrates one example of a substrate 120 ontowhich a combined coating of anodic and cathodic metals have beenco-deposited 100. The substrate may be, for example, a bioabsorbablematerial. In some variations the substrate may be an adhesive layer,e.g., when applying the coating to some medical devices. For example, anadhesive layer may be a metal layer such as an undercoating of titaniumor tantalum. The undercoating may be of any appropriate thickness (e.g.,the same thickness or smaller than the thickness of the galvanicallyreleasing coating). In some variations the undercoating is thicker thanthe coating of the non-homogeneous mixture of anodic and cathodic metalsthat are galvanically released. Although an undercoating may be used insome variations, the coatings of anodic and cathodic metals describedherein may be coated directly onto a medical device (e g, implant)without the need for an undercoating.

Although the combined coatings described herein may be used with anysubstrate (even non-bioabsorbable substrates), any of the examplesdescribed herein may be used with bioabsorbable substrates. In theexample of FIG. 2A the dimensions (thicknesses of the substrate andcoating) are not to scale. For example, the coating may be less than 100microinches thick. The substrate may be any thickness. In FIG. 2A,region B shows a portion of the coating and substrate, which isillustrated in the enlarged view of FIG. 2B.

In FIG. 2B, a portion of the substrate 120 (e.g. a bioabsorbablesubstrate) is shown coated with a combined coating 100. The anodicmetal, e.g., silver, 110 is shown forming veins or microregions withinthe cathodic metal 130. In this example, the silver is schematicallyillustrated as forming veins through a matrix of cathodic metal, e.g.,platinum, not shown to scale. The actual microdomains may be muchsmaller, and filamentous; for example, the microdomains may be on theorder of 10-1000 Angstroms (or more) across. FIG. 2C is anotherschematic illustration of a section through a portion of a combinedcoating on a substrate, showing microdomains of anodic metal (e.g.silver) 110, within a matrix of cathodic metal (e.g., platinum) 130. InFIGS. 2B and 2C the majority of the microdomains of anodic metal areconnected in continuous paths to the outer surface of the coating 100,allowing galvanic release of the anodic material.

FIG. 2D illustrates an example of the coating of FIG. 2C during thegalvanic release process, in which the implant including the substrateand the combined coating is place into the body, so that the coating isexposed to blood. As shown in FIG. 2D, the anodic metal (silver) in thecoating is progressively corroded as ions of silver are released intothe body to locally diffuse and provide regional antimicrobialtreatment. In this example the anodic metal (e.g., silver) 120 exposedto the surface is release, leaving a negative impression in the cathodicmetal 130. Regions of the cathodic metal that are left behind may remaincoated (though the substrate may also be biodegrading simultaneous withthe release of anodic metal, not shown). Typically, when the substrateis part of an implanted apparatus, the coating layer is thin enough thatany remaining cathodic metal (e.g., platinum) is small enough to beignored or easily cleared by the body.

The combined layers are generally formed by co-depositing the anodicmetal and the cathodic metal onto the substrate. For example, a combinedlayer may be formed by simultaneously sputtering the two metals onto thesubstrate to the desired thickness. For example, both silver andplatinum may be placed into a sputtering machine and applied to thesubstrate. The amount of cathodic material and anodic material may becontrolled, e.g., controlling the percentage of the coating that ifanodic metal and the percentage that is cathodic (e.g., 30%-70%anodic/70-30% cathodic, such as 40% silver/60% platinum, etc.). Thissputtering process results in a non-uniform pattern, as discussed above,and schematically illustrated in FIGS. 2B-2C, which may be observed.Alternatively, combined layers may be formed by vacuum deposition, orany other technique that can co-deposit the two (or more) metals ontothe substrate. Formation of the coating(s) may include masking, forexample, locating coatings in particular regions of the substrate.

In general, any of the substrates (e.g., bioabsorbable substrates)described herein may be applied in a pattern, including patterns ofmultiple different combined coatings. Further, coatings may be appliedover only apportion of the substrate, which may allow more localizedrelease of the antimicrobial ions and may prevent the coating frominterfering with the properties of the substrate and/or the device thatthe substrate is part of (e.g., flexibility, surface characteristics,etc.). For example, FIGS. 3A-3C show a top view of a substrate coatedwith various combined coatings (co-deposited anodic and cathodicmetals).

For example, in FIG. 3A, the surface of the substrate 210 of an implant200 that includes alternating patterns of a first combined coating 212of silver/platinum that have been co-deposited onto the substrate and asecond combined coating 214 of zinc/platinum co-deposited onto thesubstrate. In this example the first and second coating regions areformed into strips extending along the width of the substrate; the firstand second coating regions do not overlap and are not in electricalcontact with each other. Thus, the silver ions in the first coatingregion(s) 212 will be galvanically released concurrently with the zincions galvanically released from the second coating region(s) 214 whenexposed to an electrolytic bodily fluid (e.g., blood), corroding the twolayers. FIG. 3B shows another example of a pattern of a first combinedcoating 212 (e.g., silver/platinum) and a second combined coating 214(zinc/palladium) that are arranged with alternating stripes on thesurface of the substrate 210, where the stripes are end-to-end with eachother.

FIG. 3C shows another variation of a surface 210 of an implant 200 thatincludes a pattern, shown as a checkerboard pattern, of first and secondcombined coatings. In FIG. 3C, the edges of the different coatingregions may contact each other or may be separated by a channel so thatthey are not in electrical contact for the galvanic reaction. Forexample, if the first and second regions do contact each other so thatthey are in electrical contact, then the galvanic reaction may drive therelease of the zinc ions before the release of the silver ions; once thezinc has corroded, the silver ions may be released.

In general, there may be some benefit to including multiple coatings,and in particular coatings having multiple anodic metals. Theantimicrobial region around the coated implant may be made larger andthe ions may be released over a longer time period, than with a singletype of anodic coating alone.

As mentioned, the combined coatings of co-deposited anodic and cathodicmetals could be formed in any pattern.

Bioabsorbable Substrates

In some variations, the substrate is bioabsorbable and/or biodegradable.For example, the substrate may be formed as a flexible filament, and thecoating of anodic and cathodic metals that may corrode to release anodicions may allow the flexible filament to remain flexible. Galvanicrelease results in degradation (e.g., corrosion) of the coating.

The substrate onto which the combined coatings may be applied may be anyappropriate substrate, and in particular, may be a bioabsorbablesubstrate. Examples of bioabsorbable materials that may be used includespolymeric materials such as: polylactic acid (PLA),poly(lactic-co-glycolic acid) (PLGA), polyglycolide (PGA),polyglycoside-co-trimethylene carbonate (PGTMC),poly(caprolactone-co-glycoside), poly(dioxanone) (PDS), andpoly(caprolactone) (PCL), and combinations of these.

In general, bioabsorbable materials for medical applications are wellknown, and include bioabsorbable polymers made from a variety ofbioabsorbable resins; for example, U.S. Pat. No. 5,423,859 to Koyfman etal., lists exemplary bioabsorbable or biodegradable resins from whichbioabsorbable materials for medical devices may be made. Bioabsorbablematerials extend to synthetic bioabsorbable or naturally derivedpolymers.

For example, bioabsorbable substrates may include polyester orpolylactone selected from the group comprising polymers of polyglycolicacid, glycolide, lactic acid, lactide, dioxanone, trimethylenecarbonate, polyanhydrides, polyesteramides, polyortheoesters,polyphosphazenes, and copolymers of these and related polymers ormonomers. Other bioabsorbable substrates may include substrates formedof proteins (e.g., selected from the group comprising albumin, fibrin,collagen, or elastin), as well as polysaccharides (e.g., selected fromthe group comprising chitosan, alginates, or hyaluronic acid), andbiosynthetic polymers, such as 3-hydroxybutyrate polymers.

The bioabsorbable substrate may be absorbed over a predetermined timeperiod after insertion into a body. For example, the bioabsorbablesubstrate may be absorbed over hours, days, weeks, months, or years. Thesubstrate may be bioabsorbed before, during or after release of theanodic metal ions from the combined coating. In some variations therelease of the antimicrobial ions is timed to match thedegradation/absorption of the substrate. Further, the absorption of thesubstrate may facilitate the release of the anodic metal ions. Forexample, some of the bioabsorbable substrates described herein mayresult in a local pH change as the substrate is bioabsorbed; the releaseof the metal ions may be facilitated by the altered pH.

FIG. 4 shows an example of a pouch device formed from woven lengths ofbioabsorbable filament that is flexible. The filament is formed of abioabsorbable polymer, PGLA, and this bioabsorbable substrate has beencoated with the combined anodic metal/cathodic metal coating describedabove. In FIG. 4A, the pouch of PGLA fibers coated with (e.g., by vapordeposition) co-deposited silver and platinum galvanically releasessilver ions after insertion into the body. The release of anodic metalions (e.g., silver ions) is enhanced as the bioabsorbable substrate(e.g., PGLA) is hydrolyzed. Hydrolysis lowers the local pH and this mayincrease solubility of silver and bio-absorption.

The pouch of FIG. 4 may be used similarly to those described in U.S.Pat. No. 8,591,531, herein incorporated by reference in its entirety.

In general, the bioabsorbable substrate may be formed into anyappropriate shape or structure. For example, a bioabsorbable substratemay be a filament that is coated, completely or partially, by one ormore of any of the combined coatings of anodic and cathodic metalsco-deposited onto the bioabsorbable substrate. Coated strands (e.g.,filaments, strings, wires, etc.) of bioabsorbable substrate may be usedby themselves, e.g., as suture, ties, etc. within a body, or they may beused to form 2D or 3D implants, for example, by weaving them. Thecombined coatings described herein may be coated onto these structureseither before or after they have been formed. For example, a coatedfilament may be woven into a net (or into a pouch for holding animplantable device, as shown in FIG. 4), or the filament may be woveninto a net and then coated.

FIG. 5A shows an example of a filament that may be formed of abioabsorbable substrate that is coated with a combined anodic/cathodicmetal coating for galvanic release of anodic metal ions. In FIG. 5A, thefiber 500 may include uncoated regions 505 alternating with coatedregions 503. The coated region(s) may be a spiral shape around thefiber, a ring around the fiber (as shown in FIG. 5) or any otherpattern. Multiple coatings may be used (see, e.g., FIGS. 3A-3C). Thecoated fiber may retain its flexibility. In some variations the fibermay be used, e.g., as a suture.

FIGS. 5B-5D and 6 illustrate different variations of sutures that may becoated as described herein. Note that although some of these substratesforming the suture are bioabsorbable, they do not need to be. In somevariations, the suture material (the substrate onto which thegalvanically releasable coating is applied) is not biodegradable orbioabsorbable. Any variation of suture material may be used. Forexample, the suture material may be a barbed suture, as shown in FIG.5B. The barbed suture 560 may be coated 565 or otherwise treated toinclude the co-deposited coating of anodic metal (e.g., 40% by volume ofsilver) and cathodic metal (e.g., 50% by volume of platinum) arrangedwith continuous microdomains of the anodic (and/or cathodic) metalextending from the outer side of the outer surface of the coatingthrough the thickness of the coating. An entire length of suture 580 maybe coated 585, as shown schematically in FIG. 5C, or just a portion ofthe suture. The thickness of the coating may be below a threshold, whichmay help maintain the flexibility of the suture material. For example,the thickness may be between 10 microinches and 50 microinches. FIG. 5Dillustrates a suture kit including a length of suture 580 and a needle591; either or both the suture 580 and needle 591 may be coated. Thesame or different anodic metal and/or cathodic metal may be used on theneedle as the thread. For example, the needle may include the morequickly releasing nickel as the anode, while the thread, which resideslonger in the body, may use and anodic metal of silver.

FIG. 6 shows another example of a suture 600 that is coated 620 over thedistal portion of the suture, which may be used in the body. The suturemay be pre-loaded on a device (including an implant, needle, etc.). Thesuture may be formed of a bioabsorbable substrate 610 onto which thecoating is applied.

In any of the devices described herein, the coating may be made directlyonto the substrate. In some variations the coating may be made on top ofanother coating (e.g., a primer coating) which may be made to preparethe substrate for the coating. Examples of primer coatings are adhesioncoatings. An example of a primer coating may include titanium and/ortantalum undercoatings, as described above.

Additional examples of woven structures are shown in FIGS. 7-11. In FIG.7, the device 700 is formed of filaments 710 woven or arranged into amesh (shown in the enlarged view 720) that are coated with a combinedcoating (or multiple types of combined coatings) as described herein. Inthis example, the mesh formed is configured as a transvaginal mesh(intravaginal mesh) that may be used for the treatment of vaginalprolapse, for example. Slings or other anatomical support structures,either durable or biodegradable, could also be formed. These devices maygalvanically release one or more type of anionic metal ion havingantimicrobial effect. For example the mesh may be coated with a coatingof silver/platinum that is co-deposited onto the mesh or the fibersforming the mesh for galvanic release of silver from the coating.

FIGS. 8A and 8B illustrate another example of a structure, shown as awoven structure, that may also be configured as a non-woven (e.g.,solid) structure. In FIG. 8A the device 400 is a patch or plug that maybe used for treating a hernia. In this example, the patch is a wovenmesh that includes two types of combined coatings: silver/platinum andzinc/platinum in different regions over the surface of the patch. Darkerregions 803 may indicate the silver/platinum co-deposited coatingregions, while the lighter regions 805 represent co-depositedzinc/platinum regions. The entire patch outer surface or only a portionof the outer surface may be coated; in FIG. 8A, only discrete regionsare shown as coated, for the sake of simplicity. FIG. 8B shows anenlarged view illustrating the fibers forming the weave of the patch. Asshown in FIG. 8B, only some of the fibers are coated (e.g., every otherfiber of the warp); in some variations, alternating fibers in onedirection (warp) are coated with different anodic/cathodic metals, whilefibers in the opposite direction (weft) are uncoated.

FIG. 9 illustrates another example of a woven material, formed of abioabsorbable fiber, coated with the combined coatings described hereinfor galvanic release of antimicrobial metal ions. In FIG. 9, the deviceis a patch that could be used, e.g., within the knee after surgery, toreduce the chance of infection. In this example, as in FIGS. 8A and 8Babove, the patch may include filaments/fibers having different coatings(e.g., silver/platinum, zinc platinum, silver palladium, zinc palladium,etc.) and/or different regions on the patch, as shown by the light anddarker regions in FIG. 9. In some variations the patch may be wornoutside of the body, e.g., it is “implanted” by placing it over a wound,rather than entirely within the body. Blood in the wound region may actas the electrolytic fluid, allowing galvanic release of the metal ions.

Similarly, FIG. 10 illustrates a dural replacement mesh 810 that may beimplanted into a subject's head 812 to replace dural matter followingtrauma and/or surgery. The mesh may be formed of a non-bioabsorbablematerial (or a bioabsorbable material) that is coated as described aboveso as to galvanically release antimicrobial metal ions.

FIG. 11 illustrates another example of a fabric or mesh that may beimplanted into a patient as part of a surgical procedure. In FIG. 11,the mesh is a woven fabric that has been coated with one or morecombined coatings of anodic and cathodic metals co-deposited on thesubstrate (e.g., bioabsorbable substrate) for galvanic release of metalions. The material may be used, for example, as part of a large jointprocedure such as knee replacement, or spinal surgery (e.g., fixationusing rods, screws, etc.) in place of currently used antibiotic powers.For example the coated bioabsorbable mesh could be in, around, or overthe surgical site and used to galvanically release antimicrobial ionsfollowing surgery. The implant (material) would break down over time,and be absorbed following implantation (e.g., within 30 days followingthe procedure), allowing sufficient time for the patient to recover andavoid infection potentially introduced by the procedure and/or theresulting wound.

Although the devices described herein include flexible, e.g., filamentor mesh, structures, the devices may also be configured as rigid or moretraditional surgical implants, including screws, rods, staples,cannulas, etc. The substrate may be bioabsorbable.

For example, FIGS. 12A-12B shows one variation of a cannula that may beused within a body and galvanically release antimicrobial metal ions. InFIG. 12A, the cannula 300 includes a substrate 320 onto which a combinedcoating 330 is applied in a spiral pattern. The combined coatinggalvanically releases anodic metal ions (e.g., silver, zinc, copper), isincludes the anodic metal that has been co-deposited with cathodic metal(e.g., platinum, palladium, etc.). In this example, the inner surface310 of the cannula 300 may also be separately coated with a combinedcoating (the same or a different coating). FIG. 12B shows a side view ofthe catheter of FIG. 12A.

Any of the devices described herein may be used as part of a surgicalprocedure within a body (e.g., human, animal, etc.). In general, thecombined coatings described herein may be implanted into the body andmay galvanically release metal ions over an extended period of time(e.g., days, weeks, months). For example, in some variations the coatingand/or apparatus (e.g., device) may be configured to galvanicallyrelease metal ions for 30 days, 60 days, 90 days, or more.

The anti-microbial coatings, devices and systems described herein mayuse two or more types of metal ions with anti-microbial properties, suchas silver and zinc. The zone of inhibition of microbial activity/growthformed around the coated devices due to the released metal ions may beenhanced where two different types (e.g., silver and zinc) are released.The combination of zinc and silver has been observed to have asynergistic effect compared to either metal alone.

Further, when the combined coatings described herein are used incombination with a bioabsorbable (e.g., biodegradable) substrates ormaterial, the metal ions may form complexes with the byproducts ofdegradation of the substrate (e.g., polymeric substrates including PLA,PLGA, PGA) such as lactate, galactate, or glucoate. These substrates mayincrease the anti-microbial activity. For example, the range ofdiffusion of the anionic metal ions (e.g., zinc, silver, etc.) may beincreased by the creation of a complex between the metal ions and thepolymeric degradation byproduct. Further, as mentioned above,degradation of the polymers may create acidic byproducts such as lacticacid, galactic acid, and/or glycolic acid. The drop in pH and formationof the anionic byproducts may further enhance the rate of the galvanicreaction.

Thus, the apparatuses and methods above may, in some variations,generally take advantage of the use of bioabsorbable substrates that arecoated through a co-deposition process of a cathodic metal (e.g.,platinum, palladium, gold, etc.) and an anodic metal (e.g., silver,zinc, copper) to form a galvanic circuit in a fluid (e.g., electrolytic)medium to create an antimicrobial zone. The degradation of thebioabsorbable substrate may further enhance this antimicrobial zone,e.g., by forming complexes with the released metal ions to furtherdiffuse the ions as well as to alter the local pH to enhance thegalvanic reaction. In general, as described above, the combined coatingsdescribed herein can be quite thin and do not compromise theflexibility, chemic structure, strength (e.g., tensile strength) orchemical properties of the underlying substrate(s).

Examples

Any of the coatings described herein may be included on all or a portionof a medical device. For example, any of the following devices may bewholly or partially coated with a mixture of an anodic metal and acathodic metal as described herein: shunts (e.g., drainage shunts,dialysis shunts, etc.), catheters (e.g., urinary catheters,intravascular catheters, etc.), ports (e.g., portacath, etc.),artificial joints (e.g., total hip, knee, etc.), pacemakers,defibrillators (ICD), pain management implants, neuro-stimulators,neuro-pacemakers, stents, bariatric balloons, artificial heart valves,orthodontic braces, pumps (drug pumps, e.g., insulin pumps, etc.),implantable birth control devices, IUDs, etc.

Any of the coatings described herein may be included on all or a portionof a medical tool. For example, any of the following materials for usein operating on a subject may be wholly or partially coated with amixture of an anodic metal and a cathodic metal as described herein:surgical gauze, surgical sponges, wound packing materials, augmentationand/or cosmetic implants (e.g., breast/chin/facial implants), surgicalretractors, needles, clamps, forceps, and the like.

For example, FIG. 13B illustrates one example of an implant that may becoated on an outer surface with any of the antimicrobial coatingscomprising a non-homogeneous mixture of anodic and cathodic metals forgalvanic release of anti-microbial ions, as described herein, andimplant as illustrated in FIG. 13A. In this example all or just aportion of a pacemaker 1301 may be coated on an outer surface with themixture of between about 30% and 70% by volume of an anodic metal, andbetween about 30% to 70% by volume of a cathodic metal. The anodic andcathodic metals may be co-deposited on the outer substrate surface toform a non-uniform mixture of the anodic and cathodic metals, whereinthe coating comprises a plurality of microregions or microdomains ofanodic metal in a matrix of cathodic metal or a plurality ofmicroregions or microdomains of cathodic metal in a matrix of anodicmetal. In some variations different regions may be coated with differentanodic metals (e.g., forming a pattern of silver, nickel, etc. releasingregions). In some variations the electrical leads (e.g., an outersurface of the leads that are tunneled through the body, as illustratedin FIG. 13A) may be coated as described herein. Similarly, electricalleads for other devices (e.g., neurostimulators) may be coated asdescribed herein. In general, these coatings may terminate before theelectrically active regions of the lead.

For example, FIG. 13C shows a schematic depiction of an implantablepacemaker (defibrillator) system 1300 including electrodes implanted inthe heart H of a subject (patient). A cardiac stimulation anddefibrillation device 1310 is connected to the heart H via an electrodelead 1320 which comprises three lead branches or electrode supply leads1330, 1340 and 1350. Each lead branch, comprises sensing or stimulationelectrodes (which are not depicted individually) on or near the distalend thereof, and lead branch 1350 also comprises an elongateddefibrillation electrode 1360. In the arrangement shown, lead branch1330 is placed in the right atrium, lead branch 1340 is placed in theleft atrium of the heart H, and lead branch 1350 on which defibrillationelectrode 1360 is installed is placed in the right ventricle (RV). Asmentioned above, any of the leads described herein may be coated withthe mixture of between about 25% to 75% (e.g., 30% and 70%) by volume ofan anodic metal, and a cathodic metal that are co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals. The coatings may include the electrical contacts (notshown) or the contacts may not be coated. Different coatings may be used(e.g., different anodic and/or cathodic metals, different patterns ofcoating, etc.) may be used. In general, the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal. This coating may be made onthe leads without detrimentally affecting the flexibility of the leads.For example, the coating may be applied thin enough to allow the lead tobend easily, while still providing sufficient elution of antimicrobialmetal ions (e.g., silver ions) over a long time period (of weeks andmonths).

FIGS. 14A and 14B, as well as FIGS. 15A and 15B illustrate anothervariation of a type of device, a catheter such as a Venus catheter thatmay be partially or completely coated as described herein. The coatingsdescribed herein may benefit virtually any type of catheter; a Venuscatheter is generally a tube inserted into a vein in the neck (as shownin FIG. 14A), chest, or leg, e.g., near the groin, usually only forshort-term hemodialysis. In FIG. 14A, the tube splits in two after thetube exits the body. The two tubes have caps designed to connect to theline that carries blood to the dialyzer and the line that carries bloodfrom the dialyzer back to the body. A person must close the clamps oneach line when connecting and disconnecting the catheter from the tubes.Any portion (or the entire device) may be coated as described herein.For example, in FIGS. 14A and 14B, the outer surface of the catheter1405 and/or the Venus and arterial lines may be coated as describedherein.

In some devices, it may be helpful to provide a cuff or cuffs on thedevice that are specifically configured for the galvanic release ofantimicrobial ions. For example, FIGS. 15A and 15B illustrate catheters1500, 1501 for long-term vascular access that includes a cuff that maybe at least partially coated as described herein for the release ofantimicrobial ions. Adjacent to the ion-releasing cuff 1505 is atissue-ingrowth cuff 1507.

In general, the wide use of invasive medical devices, includingintravascular catheters has led to an increase in infections related tothe use of the medical device. However, intravascular catheters areoften associated with serious infectious complications, such ascatheter-related bloodstream infection (CRBSI). In fact, CRBSI isconsidered to be the most common type of nosocomial bloodstreaminfection, a finding that has been attributed to the wide use ofintravascular catheters in hospitalized patients. It is estimated that 7million central venous catheters (CVCs) will be inserted annually in theUnited States. Even with the best available aseptic techniques beingused during insertion and maintenance of the catheter, 1 of every 20CVCs inserted will be associated with at least 1 episode of bloodstreaminfection.

In the early 2000's, an estimated 300,000 cases of catheter-relatedbloodstream infection (CRBSI) occurred in the United States each year.Existing interventions to control CRBSI includeanticoagulant/antimicrobial lock, use of ionic silver at the insertionsite, employment of an aseptic hub model, and antimicrobial impregnationof catheters. However, these solutions have not proven ideal.

Several factors pertaining to the pathogenesis of CRBSI have beenidentified during the last decade. The skin and the hub are the mostcommon sources of colonization of percutaneous vascular catheters. Forshort-term, nontunneled, noncuffed catheters, the organisms migrate fromthe skin insertion site along the intercutaneous segment, eventuallyreaching the intravascular segment or the tip. Thus, it may bebeneficial to include the galvanic release coating(s) described hereinalong any (or all) portions of the catheters that are inserted into thepatient, to allow galvanic release of the antimicrobial ions (e.g.,silver, nickel, etc.) as described above. For example, FIG. 16illustrates one variation of a catheter 1601 (shown as an intravascularcatheter in this example) that has been coated along its length (or overa region) with a layer of the mixture of between about 25% to about 75%(e.g., 30% and 70%) by volume of an anodic metal, and between about 25%to about 75% (e.g., 30% to 70%) by volume of a cathodic metalco-deposited on an outer substrate surface to form a non-uniform mixtureof the anodic and cathodic metals. The coating may comprise a pluralityof microregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal. The anodic metal is galvanically releasedas antimicrobial ions when the apparatus is inserted into a subject'sbody.

Generally, long-term catheters (particularly those that are cuffed orsurgically implanted, such as those illustrated in FIGS. 15A-15B), thehub is a major source of colonization of the catheter lumen, whichultimately leads to bloodstream infections through luminal colonizationof the intravascular segment. Thus, in some variations the hub regionmay be coated as described herein.

In addition to the examples described above, other insertable orimplantable device that may be coated as described herein may includeimplantable devices such as drug delivery devices (e.g., pumps), cardiacmanagement devices (e.g., pacemakers), cochlear implants, analytesensing devices, catheters, cannulas or the like. Essentially anymedical device which experiences microbial colonization and/or biofilmformation and/or encrustation is appropriate for the practice of thepresent invention, including analyte sensing devices such aselectrochemical glucose sensors, drug delivery devices such as insulinpumps, devices which augment hearing such as cochlear implants, urinecontacting devices (for example, urethral stents, urinary catheters),blood contacting devices (including needles, blood bags, cardiovascularstents, venous access devices, valves, vascular grafts, hemodialysis andbiliary stents), and body tissue and tissue fluid contacting devices(including biosensors, implants and artificial organs). Medical devicesinclude but are not limited to permanent catheters, (e.g., centralvenous catheters, dialysis catheters, long-term tunneled central venouscatheters, short-term central venous catheters, peripherally insertedcentral catheters, peripheral venous catheters, pulmonary arterySwan-Ganz catheters, urinary catheters, and peritoneal catheters),long-term urinary devices, tissue bonding urinary devices, vasculargrafts, vascular catheter ports, wound drain tubes, ventricularcatheters, hydrocephalus shunts, cerebral and spinal shunts, heartvalves, heart assist devices (e.g., left ventricular assist devices),pacemaker capsules, incontinence devices, penile implants, small ortemporary joint replacements, urinary dilator, cannulae, elastomers,hydrogels, surgical instruments, dental instruments, tubings, such asintravenous tubes, breathing tubes, dental water lines, dental draintubes, and feeding tubes, fabrics, paper, indicator strips (e.g., paperindicator strips or plastic indicator strips), adhesives (e.g., hydrogeladhesives, hot-melt adhesives, or solvent-based adhesives), bandages,orthopedic implants, and any other device used in the medical field.Medical devices also include any device which may be inserted orimplanted into a human being or other animal, or placed at the insertionor implantation site such as the skin near the insertion or implantationsite, and which include at least one surface which is susceptible tocolonization by biofilm embedded microorganisms. Medical devices alsoinclude any other surface which may be desired or necessary to preventbiofilm embedded microorganisms from growing or proliferating on atleast one surface of the medical device, or to remove or clean biofilmembedded microorganisms from the at least one surface of the medicaldevice, such as the surfaces of equipment in operating rooms, emergencyrooms, hospital rooms, clinics, and bathrooms. Non-implanted devices foruse in a medical procedure that may be coated as described hereininclude surgical tools, e.g., suturing devices, forceps, retractors,sponges, etc.

Orthopedic devices may in particular benefit from the coatings describedherein. An implant as described herein may be used to treat bone and/orsoft tissue. In some variations the implants are bone implantsspecifically, and may be configured to support as well as treat thebone. For example, the implant may be used to secure (as a screw, nail,bolt, clamp, etc.) another member such as a plate, rod, or the like, orthe implant may itself include a support member such as a rod, plate,etc. In some variations, the implant is a soft tissue implant that isconfigured to be secured within non-bone body structures.

For example, FIGS. 17A-17C illustrate one variation of an apparatus foruse in delivering an antimicrobial ion (e.g., silver ions) to a repairsite to prevent or treat infection. In this example, apparatus includesa replaceable/removable insert that is coated. The insert maybe a meshor other material having a relatively large surface to volume ratio(e.g., large surface area). For example, FIG. 17A shows a cannulatedbone screw 1701, e.g., a bone screw having a central cannula region (notvisible in FIG. 17A) into which another device or element may beinserted, such as the bioabsorbable material 1703 (mesh) shown in FIG.17B. In FIG. 17A, the bone screw includes a distal threaded region 1705and a more proximal head 1707. In FIG. 17B the bioabsorbable mesh 1703is coated with the antimicrobial ion releasing coating such as describedherein (e.g., 30% silver/70% platinum) to a thickness of 100microinches. The cannulated bone screw 1701 may also be coated, or maynot be coated. Either before or after inserting the bone screw into thebody, the bioabsorbable insert 1703 may be inserted into the cannula ofthe bone screw 1701. This is illustrated in FIG. 17C. In practice,multiple inserts 1703 may be added to the bone screw device.

In some variations, the bone screw may itself be coated, without the useof an additional element (e.g., a bioabsorbable insert). FIGS. 18A and18B illustrate different variations of implants (e.g., bone screw) thatinclude antimicrobial ion releasing coatings as described herein. InFIG. 18A, the entire bone screw 1801 is coated with an antimicrobial ionreleasing coating comprising a mixture of between about 25% to 75%(e.g., 30% and 70%) by volume of an anodic metal, and between about 25%to 75% (e.g., 30% to 70%) by volume of a cathodic metal co-deposited onthe outer substrate surface to form a non-uniform mixture of the anodicand cathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate). In FIG. 18B, the bone screw apparatus is a screw that hasnot been completely coated, but includes differently coated regions, orregions that are both coated and uncoated. In this example the substrateis the surface of a bone screw having a striated pattern of regions ofcoatings alternating with uncoated regions.

FIGS. 19A-19B illustrate another variation in which the implant isconfigured as an orthopedic device (e.g., bone screw) having extendablemembers that can be extended out of the body of the bone screw toproject into the tissue and allow release of antimicrobial ions into thesurrounding tissue. In this variation, the implant 1901 is configured asa bone screw that is hollow or contains a hollow inner body region (notvisible in FIG. 19A) into which a replaceable/rechargeable treatmentcartridge may be inserted and/or removed. The cartridge may be itselfscrewed into the body, or it may be otherwise secured within the body.The cartridge may include one or more (e.g., a plurality) of ion releasemembers 1909 extending or extendable from the cartridge and thereforethe implant. The ion release member(s) may be configured to releasesilver, zinc or silver and zinc and may be coated with any of thecoatings described herein. In general, an ion release member may beconfigured as an elongate member such as an arm, wire, branch, or thelike. The ion release member may be a coated member such as a Nitinol orother shape-memory member coated with an antimicrobial ion releasingcoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate). As mentioned, the implant (or thetreatment cartridge portion) may include a plurality of ion releasemembers.

These implants may have one or more exit channels 1905. In general theexit channels may be openings from the inner hollow region (e.g.cannulated body) of the implant through a side wall of the implant andout, possibly in the threaded region 1907. Thus, in FIGS. 19A and 19B,the exit channel is configured to deflect the one or more ion releasemembers away from a long axis of the implant. For example, the exitchannel may be configured to deflect the one or more ion release membersagainst a thread of the outer threaded region so that it deflects awayfrom the implant. In some variations a plurality of exit channelsextending through the cannulated body 1903.

An implant such as the one shown in FIGS. 19A-19B may also include aguide (or guide element, including a rail, keying, etc.) within thechannel configured to guide or direct the one or more ion release memberout of the cannulated body 1903 from the at least one exit channel 1905.The exit channels may be configured to allow tissue (e.g., bone)ingrowth, which may help with stability of the device once implanted.For example, the exit channels may be slightly oversized compared to theion release members, permitting or encouraging in-growth. In somevariations the exit channels may be doped or otherwise include atissue-growth enhancing or encouraging factor (such as a growth factor),or may be otherwise modified to encourage tissue growth.

A treatment cartridge may be replaceable. For example, a treatmentcartridge may be configured to be removable from the cannulated body ofthe implant in situ, without removing the body of the implant from thedevice. Thus, the body of the implant may be structurally supportive(e.g., supporting the bone) while the silver-releasing cartridge armsmay be re-charged by inserting another (replacement) cartridge after theprevious cartridge has corroded. For example, an elongate cannulatedbody 1903 may be configured as bone screw (e.g., an intramedullary bonescrew).

In addition, the antimicrobial coatings described herein may also beeffective for use in non-implantable and/or insertable devices. Asmentioned above, any apparatus that may come into contact with aconductive (e.g., electrolytic) fluid, such as bodily fluids, maybenefited from the antimicrobial coatings described herein; suchapparatuses are not limited to medical devices and systems.

For example, also descried herein are garments (e.g., gloves, masks,scrubs), including facial masks (surgical masks, filters, or the like),sporting equipment (e.g., facemasks, mouthpieces, helmets, etc.), shoes(sole/shoe inserts, etc.), jewelry (necklaces, bracelets, rings, etc.)and the like, that may be coated or may include a coated region, whereinthe coating comprises any of the antimicrobial ion releasing coatingsdescribed herein, such as a coating comprising a mixture of betweenabout 25% to about 75% (e.g., 30% and 70%) by volume of an anodic metal(e.g., silver), and between about 25% to about 75% (e.g., 30% to 70%) byvolume of a cathodic metal (e.g., platinum) co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate).

FIG. 20 is one example of a non-medical application of a coating asdescribed herein. For example, an animal cage 2005 may be coated(particularly on the bottom region) with any of the antimicrobialcoatings described herein. In this example, the cage may include anantimicrobial ion releasing coatings as described herein, such as acoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate).

Similarly, any household apparatus that may be exposed to a bodily fluid(including sweat and/or mucus, as from sneezing or coughing) may becoated with any of the coatings described herein, to act as an effectiveantimicrobial barrier. For example, FIG. 21 illustrates a doorknob 2101that may be partially or completely coated with any of the antimicrobialion releasing coatings described herein on a portion that will be heldby an operator's hand 2109. Thus, this region may be coated with acoating comprising an antimicrobial ion releasing coating such as acoating comprising a mixture of between about 25% to about 75% (e.g.,30% and 70%) by volume of an anodic metal (e.g., silver), and betweenabout 25% to about 75% (e.g., 30% to 70%) by volume of a cathodic metal(e.g., platinum) co-deposited on the outer substrate surface to form anon-uniform mixture of the anodic and cathodic metals, wherein thecoating comprises a plurality of microregions or microdomains of anodicmetal in a matrix of cathodic metal or a plurality of microregions ormicrodomains of cathodic metal in a matrix of anodic metal, themicroregions or microdomains forming a continuous path of interconnectedveins of anodic metal through the coating thickness, or a continuouspath of interconnected veins of cathodic metal through the coatingthickness, wherein the continuous path extends from an outer surface ofthe coating to the substrate to the opposite side of the coating (whichmay be adjacent to the substrate). Other household fixtures that may bereadily coated include light switches, door handles/pulls, kitchenappliances (and particularly handles/controls for kitchen appliances),tabletop and/or countertop surfaces, and bathroom surfaces. For example,a toilet handle, toilet (including toilet seat and/or bowl), sink,and/or faucet may be coated as described herein.

In addition, cookware, dining wear, and/or cutlery may be coated. Suchcoatings are safe, and non-toxic, though still antimicrobial, and may beextremely long lasting (e.g., extending over months or years, dependingon coating thicknesses and use). Further, these coatings do not degradeor lose their antimicrobial activity, which is dependent primarily orexclusively on the galvanic release of ions (e.g., silver ions). Forexample, as shown in FIGS. 22A-22B, cutlery (e.g., spoons 2205, forks2207, etc.) may be coated as described herein, particularly on theportions to be placed in a user's mouth. FIG. 22B shows an example of aninfant spoon 2205′ having an elongate handle and end region 2230 formingthe spoon that is to be placed in an infant's mouth; this end region2230 may be coated specifically, e.g., with an antimicrobial ionreleasing coating as described herein, such as a coating comprising amixture of between about 25% to about 75% (e.g., 30% and 70%) by volumeof an anodic metal (e.g., silver), and between about 25% to about 75%(e.g., 30% to 70%) by volume of a cathodic metal (e.g., platinum)co-deposited on the outer substrate surface to form a non-uniformmixture of the anodic and cathodic metals, wherein the coating comprisesa plurality of microregions or microdomains of anodic metal in a matrixof cathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal through the coating thickness, or a continuous path ofinterconnected veins of cathodic metal through the coating thickness,wherein the continuous path extends from an outer surface of the coatingto the substrate to the opposite side of the coating (which may beadjacent to the substrate). The substrate may be stainless steel,polymer, or any other appropriate material. The coating is both washableand sterilizable without losing efficacy.

In some variations, the substrate is a particle, such as a micro (ornano) particle that is coated as described herein, to form a powder orother material that may be added to a device or system to provideantimicrobial activity. For example, polymeric particles may be coated(or a polymeric material may be coated and ground/broken up into smallerparticles) with any of the antimicrobial ion releasing coatingsdescribed herein, such as a coating comprising a mixture of betweenabout 25% to about 75% (e.g., 30% and 70%) by volume of an anodic metal(e.g., silver), and between about 25% to about 75% (e.g., 30% to 70%) byvolume of a cathodic metal (e.g., platinum) co-deposited on the outersubstrate surface to form a non-uniform mixture of the anodic andcathodic metals, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating to the substrate tothe opposite side of the coating (which may be adjacent to thesubstrate). The resulting particles (which may be referred to as anantimicrobial powder) may be added, e.g., into structures or ontosurfaces that will come into contact with bodily fluids.

Surface Treatments

As mentioned above, the antimicrobial coatings described herein may beapplied directly to any appropriate substrate; the substrate may, insome variations, form a part of another device or system that comes intocontact with a bodily fluid and therefore benefits from the use of theseantimicrobial coatings. For example, a coating may be made directly ontothe substrate, or it may be made onto another coating (e.g., a primercoating) which may be made to prepare the substrate for the coating.Examples of primer coatings are adhesion coatings, which may include atitanium and/or tantalum undercoating, as described above.

In some variations, the material is pretreated to prepare the surface toreceive the coating. For example, in some metals (e.g., nickel titanium,stainless steel, etc.) the surface may oxidize naturally, and it may bebeneficial to remove this oxide layer prior to applying theantimicrobial coatings described herein. For example, a substrate may beprepared by removing an oxide layer (or for other reasons) by vacuumblast cleaning with a noble gas such as argon (e.g., argon blasting orargon blast cleaning under a vacuum). Removing the thin outer oxidelayer may enhance adhesion of the coating. In general, vacuum cleaningmay be helpful, and may be performed immediately before applying thecoating (e.g., co-sputtering the anodic and cathodic materials).

Other useful pre-treatments may include applying an undercoating layer(e.g., of platinum, parylene, etc.). Such undercoatings may be appliedfirst (e.g., by sputter deposition, etc.).

One additional benefit of the coatings described herein is that they maybe applied in a relatively cool application process, e.g., in which thetemperature at which the co-deposition of the anodic material andcathodic material is applies is relatively cool (e.g., less than 150°C., less than 120° C., less than 100° C., less than 90° C., less than80° C., less than 70° C., less than 60° C., less than 50° C., etc.). Thetemperature of application may be adjusted along with the time to formthe coating (e.g., cooler application may generally take longer). Coolerapplication may be particularly beneficial when the substrates to whichit is being applied is temperature sensitive, or when it is beingapplied to a device (including devices having active/electronic parts)that are rate below a predetermined temperature.

Post-Coating Treatments

Any of the apparatuses described herein (e.g., any of the coatingsdescribed herein) maybe treated to enhance the galvanic release ofantimicrobial ions (e.g., silver). Such treatments may be referred to aspost-coating treatments because they may be performed after the coatinghas been applied. For example, any of the apparatuses described hereinmay include coatings that are treated to enhance the surface area bycracking, fracturing, or otherwise roughening the coating, which mayincrease the exposed surface area of the coating.

Post-coating treatments may include thermal treatments (e.g., exposingthe surface to a cooler temperature to crack or fracture the coating),and/or energy (e.g., ultrasound, RF, etc.) to fracture the surface. Forexample, in some variations the coating may be connected to anoscillating high voltage source that makes cracks in the coating. Forexample, FIGS. 23A and 23B illustrates a variation of a substrate 2320(similar to the example shown in FIGS. 2A-2D) has been coated with anantimicrobial ion releasing coating 2300 as described above. In thisexample, after co-depositing the anodic and cathodic metals, the coatedapparatus has been treated to fracture the coating, formingbreaks/fractures 2350 (shown schematically in FIG. 23B from the enlargedregion B in FIG. 23A). In this example, the fractures 2350 are formedvertically into the coating to expose more of the anodic metal andcathodic metal, potentially allowing for greater (and/or faster) releaseof anodic antimicrobial ions.

Thus, in any of the apparatuses described herein, the coatings may befractured (cracked, etc.) to enlarge the surface area. Cracks orfractures may be formed of a predetermined density and/or depth. Forexample, the coating may be fractured or may include cleavage regionsinto the thickness of the coating at a density of between 0.01% and 80%of the surface (e.g., greater than 0.1%, greater than 1%, greater than5%, greater than 10%, greater than 15%, etc.). The percentage offracturing typically results in an increase the in the surface area, andmay therefore be referred to as a percentage increase in the surfacearea. For example the percent increase in the surface area due tofracturing the surface may result in an increase of greater than 0.25times the un-fractured surface area (e.g., a 25% or greater surface areafollowing fracturing). In some variations the surface area may beincreased greater than 0.3 times (e.g., 0.35× or greater, 0.40× orgreater, 0.45× or greater, 0.5× or greater, 0.6× or greater, 0.75× orgreater, 0.8× or greater, 0.9× or greater, 1× or greater, 2× or greater,3× or greater, etc.).

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements, these features/elements should not be limitedby these terms, unless the context indicates otherwise. These terms maybe used to distinguish one feature/element from another feature/element.Thus, a first feature/element discussed below could be termed a secondfeature/element, and similarly, a second feature/element discussed belowcould be termed a first feature/element without departing from theteachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical rangerecited herein is intended to include all sub-ranges subsumed therein.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

What is claimed is:
 1. An apparatus that galvanically releasesantimicrobial ions, the apparatus comprising: a substrate surface; and acoating on the outer substrate surface, the coating comprising a mixtureof between about 25% and 75% by volume of an anodic metal, and betweenabout 25% to 75% by volume of a cathodic metal co-deposited on thesubstrate surface, wherein the coating comprises a plurality ofmicroregions or microdomains of anodic metal in a matrix of cathodicmetal or a plurality of microregions or microdomains of cathodic metalin a matrix of anodic metal, the microregions or microdomains forming acontinuous path of interconnected veins of anodic metal through thecoating thickness, or a continuous path of interconnected veins ofcathodic metal through the coating thickness, wherein the continuouspath extends from an outer surface of the coating through the coating toan opposite side of the coating; wherein the anodic metal isgalvanically released as antimicrobial ions when the apparatus isexposed to a bodily fluid.
 2. The apparatus of claim 1, wherein lessthan 30% of the anodic metal is fully encapsulated within the matrix ofcathodic metal and connects through a microregion or microdomain ofanodic metal to the outer surface of the coating.
 3. The apparatus ofclaim 1, wherein less than 20% of the anodic metal is fully encapsulatedwithin the matrix of cathodic metal and connects through a microregionor microdomain of anodic metal to the outer surface of the coating. 4.The apparatus of claim 1, wherein the anodic metal comprises both zincand silver.
 5. The apparatus of claim 1, wherein the anodic metalcomprises silver, zinc or copper.
 6. The apparatus of claim 1, whereinthe cathodic metal comprises one or more of: palladium, platinum, orgold.
 7. The apparatus of claim 1, wherein the cathodic metal comprisesone or more of: palladium, platinum, gold, molybdenum, titanium,iridium, osmium, niobium and rhenium.
 8. The apparatus of claim 1,wherein the coating comprises the anodic metal and the cathodic metalthat have been vapor-deposited onto the substrate so that the anodicmetal is not encapsulated by the cathodic metal.
 9. The apparatus ofclaim 1, wherein the surface is an outer surface of one of: a pacemaker,defibrillator, neurostimulator, or ophthalmic implant.
 10. The apparatusof claim 1, wherein the surface is an outer surface of one of: animplantable shunt, an artificial joint, a hip implant, a knee implant, acatheter, a stent, an implantable coil, a pump, an intrauterine device(IUD), a heart valve, a surgical fastener, a surgical staple, a surgicalpin, a surgical screw, an implantable electrical lead, or an implantableplate.
 11. The apparatus of claim 1, wherein the surface is an outersurface of one of: a retractor, a bariatric balloon, an orthodonticbrace, a breast implant, a surgical sponge, a gauze, or a wound packingmaterial.
 12. The apparatus of claim 1, wherein the coating isfractured.
 13. The apparatus of claim 1, wherein the coating isfractured so that a surface area of the coating is increased by at least25% compared to the surface area of the coating in an unfractured state.14. A method of galvanically releasing antimicrobial ions to form anantimicrobial zone around an implant that is inserted into a subject'stissue, the method comprising: inserting into the subject's tissue anapparatus comprising a coating on an outer surface, the coatingcomprising a mixture of between about 25% and 75% by volume of an anodicmetal, and between about 25% to 75% by volume of a cathodic metalco-deposited on the substrate surface, wherein the coating comprises aplurality of microregions or microdomains of anodic metal in a matrix ofcathodic metal or a plurality of microregions or microdomains ofcathodic metal in a matrix of anodic metal, the microregions ormicrodomains forming a continuous path of interconnected veins of anodicmetal through the coating thickness, or a continuous path ofinterconnected veins of cathodic metal through the coating thickness,wherein the continuous path extends from an outer surface of the coatingthrough the coating to an opposite side of the coating; galvanicallyreleasing antimicrobial ions of the anodic metal from the coating. 15.The method of claim 14, wherein inserting comprises inserting apacemaker.
 16. The method of claim 14, wherein inserting comprisesinserting a defibrillator.
 17. The method of claim 14, wherein insertingcomprises inserting a neurostimulator.
 18. The method of claim 14,wherein inserting comprises inserting one of: an implantable shunt, anartificial joint, a hip implant, a knee implant, a catheter, a stent, animplantable coil, a pump, an intrauterine device (IUD), a heart valve, asurgical fastener, a surgical staple, a surgical pin, a surgical screw,an implantable electrical lead, or an implantable plate.
 19. The methodof claim 14, wherein galvanically releasing antimicrobial ions from thecoating comprises galvanically releasing ions of silver, zinc or silverand zinc.
 20. The method of claim 14, wherein the antimicrobial zonearound the implant is sustained for greater than two weeks.
 21. Themethod of claim 14, wherein the antimicrobial zone around the implant issustained for greater than thirty days.